ABSTRACT Lung cancer is the leading cause of cancer deaths, with a 5-year survival rate of <15%. This alarming prognosis makes clear the urgent need for new efficacious agents for its treatment. Phospho-sulindac (PS), a novel compound developed by us, inhibits the growth of lung cancer xenografts by 87-103%, eliminating, in one study, 3/7 lung cancer tumors. In addition to its remarkable efficacy, PS has an exceptional safety profile. Thus PS has a strong potential of becoming an efficacious agent for the treatment of lung cancer. Our preliminary data indicate that the mechanism of the anti-cancer effect of PS is, in its essence, the following: PS induces oxidative stress, which activates redox-sensitive signaling cascades, which in turn block cell cycle progression, inhibit proliferation and induce apoptosis; the end result is inhibition of tumor growth. The development of oxidative stress by PS is due to: a) activation of NADPH oxidase, which generates the free radical superoxide anion; and b) suppression of several members of the antioxidant system of the cell, both enzymatic (the thioredoxin system, peroxiredoxin, cytoglobin, superoxide dismutase) and chemical (glutathione).These effects increase rapidly the cellular levels of reactive oxygen species (ROS) shifting the redox balance towards oxidative stress. In vivo, co-administration of the antioxidant N-acetyl-cysteine and PS suppresses oxidative stress and eliminates the anticancer effect of PS on lung cancer xenografts. Our hypothesis is that PS is a highly effective and safe agent for the treatment of lung cancer acting predominantly by inducing oxidative stress. To evaluate this hypothesis, we propose the following specific aims: 1) Assess the efficacy of PS against lung cancer in animal tumor models: We will expand the efficacy studies to include xenografts of additional cell lines mirroring the genetic subtypes of lung cancer and a transgenic model of lung cancer. 2) Validate efficacy results in patient-derived lung cancer xenografts. They provide excellent prediction of drug efficacy in humans; we will study tumors with KRAS or EGFR mutations. And 3) Study in vitro and in vivo the molecular targets involved in the induction of oxidative stress by PS and the downstream signaling pathways that mediate its anticancer effect. We will evaluate the main contributors to oxidative stress and signaling pathways downstream of oxidative stress.